Background: Cannabis use and childhood trauma associated with a genetic predisposition may increase the risk of psychosis. Genetic variations in N-methyl-d-aspartate (NMDAR) and cannabinoid type 1 (CB1) receptor genes have contributed to the development of psychoses. However, the neurobiological processes underlying this relationship (cannabis use, childhood trauma and variants of NMDAR and CB1 genes) are unknown in first-episode psychosis patients (FEP) and early stages of the disease. Aims: Study 1: to investigate the interaction and association of single nucleotide variants of NMDAR genes (GRIN1, GRIN2A and GRIN2B) and CB1 gene (CNR1) and childhood trauma in relation to the use of cannabis to understanding the mechanisms of psychosis; Study 2 (including BEPE): to investigate the interaction and association among cannabis use, childhood trauma and genetic variants on peripheral markers (gene expression and DNA methylation) of NMDAR and CB1 genes, as to develop an in vitro model of DNA methylation to identify biological markers for psychosis. Methods: Study 1 (data collected): We will include blood samples of FEP patients (n=143), non-affected siblings (n=73) and community-based controls (n=286) recruited from the Ribeirão Preto catchment area. Study 2 (new study): We will isolate leukocytes from blood in patients at early stages of psychosis and controls (n=100/group). The Cannabis Experience Questionnaire-Modified Version will assess the clinical characterization of cannabis use, childhood trauma using Childhood Trauma Questionnaire, variants using a personalized genotyping matrix from Illumina, gene expression by RT-qPCR and DNA methylation by pyrosequencing. The associations between the genetic/molecular profiles of NMDAR and CB1 genes, cannabis use and childhood trauma will be assessed through linear analyses of mixed-effect and adjusted logistic regression models. Expected results: Individuals who use cannabis and a history of childhood trauma associated with relevant variants of NMDAR and CB1 genes will be more vulnerable to psychosis, showing altered DNA methylation and decreased NMDAR and CB1 gene expressions.
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